The present invention relates to methods of treating patients who are refractory to non-adenosine modifying diuretics by administering a combination of a non-adenosine modifying pharmaceutical composition and an adenosine A1 antagonist. The claimed methods are useful in any condition which interferes with the pre-renal signaling in such patient.
Adenosine is an extracellular messenger generated by all cells in the body. Adenosine itself, substances that mimic the actions of adenosine, and substances that antagonize its actions have important clinical applications. Adenosine receptors are divided into subtypes designated for example as A1, A2, etc.
In most organ systems (e.g. the heart), adenosine is present exclusively during periods of metabolic stress, to mediate adaptive responses to the insult which precipitated its production and release. The kidney also releases excess adenosine in response to ischemic and toxic stimuli. In addition, however, the kidney produces adenosine constitutively to regulate glomerular filtration and electrolyte reabsorption mediated by the adenosine A1-receptor system. Adenosine receptors, when activated, can elicit either vasoconstriction (A1) or vasodilation (A2).
The A1 adenosine receptor has been found to govern the vasoconstriction response of the efferent (preglomerular) renal arteriole. Adenosine and other adenosine agonists cause a reduction in the blood flow to the kidney, and thus a reduction in the glomerular filtration rate. Thus, blocking the effects of adenosine will produce a rise in the glomerular filtration rate, and a corresponding increase in the rate of urine formation. In recent years, more selective and potent adenosine receptor antagonists have been identified, and been associated with diuretic affects.
Congestive heart failure affects millions of patients every year. Most of these patients are currently treated with diuretics to eliminate or reduce the retention of salt and water in the lungs and peripheral tissues. This pulmonary and peripheral edema causes the shortness of breath and uncomfortable ankle swelling which are common symptoms in heart failure patients. As the disease progresses, responsiveness to the currently available diuretics diminishes, and the edema becomes increasingly difficult to treat.
Problematic fluid retention is also caused by other conditions such as, for example, chronic liver diseases like cirrhoses, which in turn, produce associated abnormalities in renal function. These patients accumulate large volumes of intra-abdominal fluid, or ascites. Ascites fluid is notoriously refractory to mobilization with available diuretics. In current practice, therefore, patients are hospitalized every 1-2 months for drainage of ascites fluid through a catheter inserted directly into the abdominal cavity, i.e. paracentesis.
Diuretic resistance in conditions such as those discussed above often develops because the fraction of filtered sodium reabsorbed at the proximal tubule of the nephron increases dramatically in these patients. Consequently, diuretics acting to interrupt sodium excretion only at more distal portions of the nephron can have little or no diuretic affect.
Thus, there remains a need for compositions and methods for treating patients suffering from diuretic resistance and associated reduced renal function by regulating their body fluid and kidney function.
The presently claimed invention relates to compositions comprising a pharmaceutically effective amount of an adenosine A1 receptor antagonist and a non-adenosine modifying diuretic. The antagonist is preferably a highly potent and selective antagonist against the A1 receptor, and more preferably is BG9719, salts, isomers, esters or derivatives thereof. The diuretic can be any non-adenosine modifying diuretic, but is preferably selected from the group consisting of loop, distal or thiazide diuretics, more preferably selected from hydrochlorothiazides, furosemide, torsumide, bumetadine, thacrynic acid, piretanide, norsemide, spironolactone, tramterene and amiloriduthiazides.
The novel methods of the invention comprise the step of administering a first pharmaceutical composition comprising a therapeutically effective amount of an adenosine A antagonist in combination with a second pharmaceutical composition comprising a non-adenosine modifying diuretic. The second pharmaceutical composition can be any composition capable of inducing a diuretic effect in a patient having excess fluid. Preferably, the antagonist is a highly potent and selective antagonist against the A1 receptor, more preferably, the antagonist has a nanomolar binding affinity for the A1 receptor, and is at least 100 times more selective toward the A1 receptor than the A2a receptor. Most preferably the antagonist is BG9719, salts, isomers, esters or derivatives thereof. The diuretic can be any non-adenosine modifying diuretic, but is preferably selected from the group consisting of loop, distal or thiazide diuretics, more preferably selected from hydrochlorothiazides, furosemide, torsumide, bumetadine, thacrynic acid, piretanide, norsemide, spironolactone, tramteren and amiloriduthiazides. It is most preferable to use furosemide. In certain embodiments, the pharmaceutical compositions and methods of the invention may comprise a third component which is a diuretic which acts on a different portion of the nephron than the second pharmaceutical composition. In some circumstances, beneficial effects may result from using one or more diuretics in the second pharmaceutical composition.
The claimed methods encompass the administration of the first and second pharmaceutical compositions sequentially, or in certain instances substantially simultaneously. The preferred method comprises administering to a patient the second pharmaceutical composition comprising a non-adenosine modifying diuretic for a period of time until the patient""s responsiveness to that diuretic begins to decline, or kidney function begins to decline, or both. The first pharmaceutical composition comprising the highly potent and selective antagonist can then be administered to the patient to restore diuretic responsiveness and to restore, or improve the kidney function, often as measure by a rise in GFR.
In alternative embodiments the claimed methods comprise the substantially simultaneous administration of the first and second pharmaceutical compositions. These compositions may be combined into a single tablet or formulation for ease of administration, or may comprise separate formulations so that the dosages of each may be varied to adjust to the needs of the particular patient being treated.
In the most preferred compositions and methods of the invention, the adenosine antagonist is BG9719, salts, isomers, esters or derivatives thereof, in addition to furosemide.